The major goal of this project is to learn more about the physiology of human motor control using transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (TES). An important theme of this work has been to understand the plasticity of the motor system in a number of circumstances. In our study of hemiplegia after stroke we have been evaluating patients with subcortical lesions. In most of these patients cortical excitability is much reduced (despite no such reduction on functional PET scans). We are beginning some therapeutic trials in stroke rehabilitation and will include physiological studies. In an on-going trial, we are trying to reverse "learned non-use" with appropriate physical therapy. TMS is being used in trials as a possible therapeutic modality. However, attempts to speed up movement in patients with Parkinson's disease have not succeeded. Some studies are being done in psychiatric disorders. In patients with obsessive compulsive disorder (OCD), we have found abnormal absence of intracortical inhibition at short (3-6 ms) intervals. We tested whether the organization of the human sensorimotor cortex deafferented by temporary ischemic nerve block of the contralateral forearm is more modifiable than a 'normal' cortex. As modifying inputs, we used either repetitive transcranial magnetic stimulation of the deafferented motor cortex or repeated voluntary contractions of a muscle proximal to the nerve block. We found that these inputs, while subthreshold for producing changes in the cortex when given alone, induced a significant enhancement of the ischemia-induced increase in the excitability of the "stump" representation when given during ischemia. We conclude that the deafferented cortex is more modifiable than a 'normal' cortex, a phenomenon that might be used in the setting of neurorehabilitation. We used the forearm ischemia model in combination with CNS-active drugs and repetitive magnetic stimulation of the 'plastic' motor cortex to study mechanisms of the ischemia-induced increase in the excitability of the "stump" representation. We found that a single oral dose of a benzodiazepine, a voltage-gated sodium channel blocker or a NMDA receptor antagonist suppressed this form of plasticity. We conclude that the mechanisms involved in this rapid increase of motor cortical excitability likely include a removal of local GABAergic inhibition and long-term potentiation like mechanisms. A study performed in patients with amputations suggest that motor reorganization following lower-limb amputation occurs predominantly at the cortical level and that the mechanisms involved are likely to include reduction of GABAergic inhibition. We used single pulse transcranial magnetic stimulation to explore the existence of a significant ipsilateral corticospinal pathway in adult healthy volunteers. We were able to elicit ipsilateral motor evoked potentials in a small hand muscle in every subjects. These responses had a higher threshold, were delayed by several milliseconds and elicited from more antero-lateral sites of the motor cortex compared to the contralateral response which is mediated via the crossed monosynaptic corticospinal tract. The findings on the ipsilateral response are best compatible with an oligosynaptic ipsilateral pathway, for instance a cortico-reticulospinal or cortico-propriospinal projection. We demonstrated that fatiguing isometric exercise leads to reduced motor potentials as evoked by TMS, and planned a series of experiments to study the pharmacology of this phenomenon of "central fatigue."